Identification of HPr kinase/phosphorylase inhibitors: novel antimicrobials against resistant Enterococcus faecalis

Sandeep Kumar, Rajendra Bhadane, Shruti Shandilya, Outi M.H. Salo-Ahen, Suman Kapila*

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

3 Citations (Scopus)
51 Downloads (Pure)

Abstract

Enterococcus faecalis, a gram-positive bacterium, is among the most common nosocomial pathogens due to its limited susceptibility to antibiotics and its reservoir of the genes coding for virulence factors. Bacterial enzymes such as kinases and phosphorylases play important roles in diverse functions of a bacterial cell and, thus, are potential antibacterial drug targets. In Gram-positive bacteria, HPr Kinase/Phosphorylase (HPrK/P), a bifunctional enzyme is involved in the regulation of carbon catabolite repression by phosphorylating/dephosphorylating the histidine-containing phosphocarrier protein (HPr) at Ser46 residue. Deficiencies in HPrK/P function leads to severe defects in bacterial growth. This study aimed at identifying novel inhibitors of E. faecalis HPrK/P from a commercial compound library using structure-based virtual screening. The hit molecules were purchased and their effect on enzyme activity and growth of resistant E. faecalis was evaluated in vitro. Furthermore, docking and molecular dynamics simulations were performed to study the interactions of the hit compounds with HPrK/P. Among the identified hit molecules, two compounds inhibited the phosphorylation of HPr as well as significantly reduced the growth of resistant E. faecalis in vitro. These identified potential HPrK/P inhibitors open new research avenues towards the development of novel antimicrobials against resistant Gram-positive bacteria.

Original languageEnglish
Pages (from-to)507-520
Number of pages14
JournalJournal of Computer-Aided Molecular Design
Volume36
Issue number7
Early online date9 Jul 2022
DOIs
Publication statusPublished - Jul 2022
MoE publication typeA1 Journal article-refereed

Keywords

  • E. faecalis
  • HPr
  • HPrK/P
  • Molecular docking
  • Molecular dynamics simulation
  • Structure-based drug design
  • Virtual screening

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